Stenotrophomonas Maltophilia, commonly known as S. Maltophilia is an aerobic, gram negative emerging Multi-Drug Resistant global opportunistic pathogen. The increasing incidence of nosocomial and community-acquired S. Maltophilia infections is of particular concern for immunocompromised individuals, as this bacterial pathogen is associated with a significant fatality/case ratio and has emerged as an important nosocomial pathogen associated with crude mortality rates ranging from 14 to 69% in patients with bacteremia.
S. maltophilia exhibits resistance to a broad array of antibiotics, including TMP-SMX, β-lactam antibiotics, macrolides, cephalosporins, fluoroquinolones, aminoglycosides, carbapenems, chloramphenicol, tetracyclines, polymyxins, cefepime, ticarcillin-clavulanate, ceftazidime, and piperacillin-tazobactam.
Therefore S. Maltophilia is emerging as Multi-Drug Resistant pathogen worldwide, capable of causing serious respiratory tract infections, bloodstream and urinary infections. Some of the common infections caused by this notorious pathogen include pneumonia, blood stream infection, skin infection, surgical site related infections, urinary tract infections, endocarditis meningitis, intra-abdominal infections, co-morbid illness, endophthamitis and cystic fibrosis (a hereditary metabolic disorder of the exocrine glands that mainly affects the pancreas, respiratory system and sweat glands).
According to one study, the drug resistance of S. Maltophilia is increasing at the rate of 10% to 15% in USA and European countries making the treatment of S. Maltophilia infections significantly difficult with reduced treatment options.
Novel compound [(S)—N-[[3-[4-fluoro-3-morpholino phenyl]-2-oxooxazolidin-5-yl] methyl] acetamide] of Formula-I was disclosed in Indian Patent Application No. 5063/CHE/2013 and corresponding PCT/IN2014/000018 of the applicant which are incorporated herein by reference. This compound belongs to the oxazolidinone class of drugs which are known to have potent antimicrobial activity against a number of human and veterinary pathogens, including anaerobic organisms such as bacteroides and clostridia species and acid fast organisms such as mycobacterium tuberculosis and mycobacterium avium, multi-drug resistant Gram-positive bacteria, including methicillin resistant Staphylococcus aureus (MRSA), Staphylococcus epidermitis (MRSE), penicillin-resistant Streptococcus pneunoniae (PRSP) and vancomycin-resistant enterococci (VRE).
The oxazolidinones class of antibacterials possess a unique mechanism of inhibiting bacterial protein synthesis. Linezolid is one of the most important oxazolidinone class of drug having potent antibacterial activity and was the first oxazolidinone to be approved for clinical use with potential antibacterial activity against many important resistant pathogens. However, S. Maltophilia has exhibited resistance against Linezolid also and therefore, inventors were looking towards development of new antibacterial compound which could be effective against the S. Maltophilia and other Multi-Drug Resistant pathogens.
The inventors have developed a novel compound [(S)—N-[[3-[4-fluoro-3-morpholino phenyl]-2-oxooxazolidin-5-yl] methyl] acetamide] of Formula-I which was disclosed in Indian Patent Application No. 5063/CHE/2013 and corresponding PCT/IN2014/000018. In further antimicrobial studies on compound-I, it was observed that this compound had shown immense potential to treat the infections caused by the Multi-Drug Resistant S. Maltophilia pathogen and against a broad spectrum of gram positive and gram negative pathogens and has also shown promising results in Single Dose Acute Toxicity tests conducted on this compound. The compound has shown excellent biological activities against S. Maltophilia which has developed resistance against a large number of antibiotics including some of the known and widely used oxazolidinone derivatives.